Genetic factors contribute significantly to autism susceptibility, but the heterogeneity of autism and autism spectrum disorders poses a challenge for genetic studies. Research from several groups suggests that studying cognitive or behavioral components of autism, or endophenotypes may aid in identification of more homogeneous subgroups and hasten the identification of genetic loci underlying this condition. We hypothesize that speech and language related endophenotypes may underlie several of the suggestive or probable autism linkage peaks. To uncover the extent to which speech and language related endophenotypes contribute to autism susceptibility loci, data and subjects from two ongoing projects, including Project I in this center proposal, will be used to identify and narrow language-related QTLs to a region small enough to permit a large scale gene by gene search. Our ongoing work in the AGRE resource has identified several autism peaks at the level of possible or probable linkage. In addition, we have identified one major and several minor linkage peaks related to speech and language delay in autistic siblings in this large autism cohort (AGRE). Parents and unaffected siblings in this sample have already been genotyped and, thus, have the potential to add power to the analysis without the requirement for additional genotyping. Therefore, we propose to evaluate parents and non-autistic sibs for a history of speech delay using an efficient questionnaire methodology in at least 330 AGRE families, bringing the number of sib pairs available for analysis to 690. QTL methodologies will be used to identify loci in the entire sample, as well as a subgroup of families stratified according to a parental history of developmental language-related problems. Independent confirmation of the speech and language related loci identified in AGRE will be assessed using the prospectively collected cohort of 180 infant-sib/autistic child pairs studied for language and social communication development in Project I. This provides the advantage of testing the language-related loci in an independent sample that is prospectively studied for receptive and expressive language and speech assessment, rather than depending entirely on retrospectively collected historical data. In addition, the availability of data on both receptive and expressive language will allow preliminary refinement of the language phenotype underlying these loci. Multivariate analysis will be used to explore the relationships among social communication, language, and outcomes of the children in Project I, and to explore the extent to which identified genetic loci have pleiotropic effects. Candidate genes within narrow linkage regions will be tested for association using SNP genotyping and family based association methods.